A single-center prospective randomized study was conducted at the Andrology Unit of Tanta University in Egypt between November 2020 and November 2022 to evaluate the efficacy and safety of botulinum-A toxin injection into BS in the treatment of lifelong PE in a sample of Egyptian patients. The study was conducted in accordance with the declaration of Helsinki. The study was approved by the institutional review board of Tanta University (IRB approval number: 34296/11/20).

Patients with lifelong PE with stable monogamous female sexual partners for at least 6 months and declared the ability to follow study instructions and complete study assessment tools were included. Those who suffer from bleeding tendencies, hypersensitivity to botulinum-A toxin or muscular weakness as myasthenia gravis; or suffer from PE secondary to erectile dysfunction, genital infection or psychic stress were excluded from the study. It is to be noted that erectile dysfunction was excluded using the International Index of Erectile Function-5 (IIEF-5) [8, 9].

All patients were evaluated by medical history (age, medical co-morbidities, onset of the condition, duration, previous medications), physical examination to exclude any anomalies in the external genitalia. Also, they were objectively evaluated using intravaginal ejaculatory latency time (IELT), the Premature Ejaculation Profile (PEP) score and female partner’s satisfaction score.

The PEP score includes 4 individual measures: self-perceived control over ejaculation, personal distress related to ejaculation, contentment with sexual intercourse, and interpersonal challenges associated with ejaculation. Each of these measures is evaluated using a five-point response scale. This instrument finds utility in appraising various domains of PE as well as its treatment efficacy [10].

Regarding the IELT, the partner was requested to run a calibrated stopwatch on vaginal penetration and stop it on extra or intravaginal ejaculation or withdrawal of the penis without ejaculation at the end of sexual intercourse. The IELT considered for statistical analysis was the geometric mean of the last 3 sexual acts’ IELT at each time point i.e., pre-injection and 1, 3 and 6 months after injection. It is to be mentioned that all patients received training on how to record IELT using calibrated stopwatch prior to enrollment in the study. Regarding female partner’s satisfaction, it was assessed using a 1 to 5 Likert scale where 1 is very dissatisfied, 2 is dissatisfied, 3 is neither satisfied nor dissatisfied, 4 is satisfied and 5 is very satisfied.

Independent randomization (in 1:1 ratio) was conducted by a third party (not involved in the study) using a computer-generated random table with stratification according to botulinum-A or placebo. The treating physicians were aware of the randomization, whilst patients were unaware.

Eligible patients have been asked to stop any medical treatment that could affect their sexual function e.g., phosphodiesterase 5 inhibitors and medications for lifelong PE; for at least 1 month before injection as well as 6 months thereafter. BS injection with 100 U of botulinum-A toxin in 10 ml of saline was performed in group I (treatment) whereas Group II (placebo) was injected with 10 ml of saline in BS. Injection was done in lithotomy position, under ultrasound guidance using the superficial probe to localize the site of injection; by experienced uro-andrologist. No anesthesia was required as the injection was well tolerated by all patients. Injection was done under complete aseptic condition, in 2 points, one on each side of the midline in order to infiltrate the right and left muscles. The drug was distributed all through the muscle using fanning technique and ultrasound guidance ensured accuracy of infiltration (Fig. 1A, B).

A Pre-injection skin marks, B US image of bulbospongiosus muscle identification during drug injection.

The primary outcome was to assess the effect of the injection of botulinum-A toxin in BS on the PE status. This was performed by reporting changes in IELT, PEP and female partners’ satisfaction before treatment and at 1, 3 and 6 months thereafter. We compared the changes in the mean values between both groups at the determined follow-up points. The second outcome was to assess the safety of the drug injection by reporting any adverse events during or after injection in both groups.

Pre allocation sample size estimation was not performed because of unavailability of previous similar studies and the expected limited number of eligible patients. Post-hoc sample size assessment was performed considering the mean difference in PEP score changes between both groups at 1 month (effect size: 0.6) and alpha error 0.05. The estimated power was 80%. The per-protocol analyses were performed to avoid the impact of dropped-out cases. Independent sample t test was used to compare the mean scores between both groups at different intervals. The changes in the mean PEP, IELT and female satisfaction scores at different time points in each group were done using paired sample t test. The comparison of the changes in the mean scores in relation to baseline value between both groups was done by repeated measure ANOVA test. Statistical analysis was performed using IBM SPSS software v. 21. A P value of <0.05 was taken to indicate statistical significance.